Abstract
Circulating trimethylamine N-Oxide (TMAO) levels predict cardiovascular disease (CVD), possibly by impacting on cholesterol metabolism and oxidative stress. Because hepatic TMAO production is regulated by insulin signalling and it is unclear whether and to what extent circulating TMAO levels associate with CVD risk, independently of insulin resistance and its important determinants fatty liver and visceral obesity, we have now addressed this question in 220 subjects who participated in the Tübingen Lifestyle Intervention Program. Visceral fat mass (r = 0.40, p < 0.0001), liver fat content (r = 0.23, p = 0.0005) and TMAO levels (r = 0.26, p < 0.0001) associated positively, and insulin sensitivity associated negatively (r = −0.18, p = 0.009) with carotid intima-media thickness (cIMT). Higher TMAO levels (std.−Beta 0.11, p = 0.03) predicted increased cIMT, independently of age, sex and visceral fat mass. While during the lifestyle intervention most cardiovascular risk parameters improved, mean TMAO levels did not change (p = 0.18). However, cIMT decreased significantly (p = 0.0056) only in subjects in the tertile with the largest decrease of TMAO levels (>20%). We provide novel information that increased serum TMAO levels associate with increased cIMT, independently of established cardiovascular risk markers, including insulin resistance, visceral obesity and fatty liver. Furthermore, the decrease of cIMT during a lifestyle intervention may be related to the decrease of TMAO levels.
Highlights
The identification of a meta-organismal pathway involving dietary intake, gut microbiota and liver metabolism has raised much interest in the cardiometabolic field of research[1]
Given that hepatic flavin mono-oxygenase 3 (FMO3) expression is under the negative control of insulin, hepatic FMO3 gene expression is elevated in obese and insulin resistant mice and, to a lesser extent in obese and patients with diabetes[13], and fasting glucose levels were found to correlate positively with trimethylamine N-Oxide (TMAO) levels in humans[2], the question arises to what extent circulating TMAO levels associate with precisely measured insulin sensitivity in humans
Increased generation of TMAO is thought to represent a major pathomechanism contributing to increased cardiovascular disease (CVD) risk[1]
Summary
The identification of a meta-organismal pathway involving dietary intake, gut microbiota and liver metabolism has raised much interest in the cardiometabolic field of research[1]. The group of Stanley Hazen provided strong support that metabolism of dietary phosphatidylcholine and L-carnitine by intestinal microbiota, resulting in the formation of the metabolite trimethylamine and its hepatic conversion to trimethylamine N-oxide (TMAO), induces atherosclerosis and that high TMAO levels predict an increased risk of cardiovascular disease (CVD)[2,3,4,5]. Another group found elevated TMAO concentrations to independently predict coronary atherosclerosis and mortality in patients with chronic kidney disease[6]. These subjects were at risk for type 2 diabetes, underwent precise measurements of glucose and lipid metabolism and measurement of the carotid intima-media thickness (cIMT) as an early marker of atherosclerosis, and participated in a lifestyle intervention trial
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